Drug delivery apparatus

ABSTRACT

A drug delivery apparatus comprising: a drug delivery device for selectively delivering drug-laden air or air not laden with the drug; a sensor for monitoring the breathing pattern of a patient; a controller arranged to control the drug delivery device to deliver drug-laden air in pulses which begin when the patient is monitored by the sensor to begin inhalation, the pulses having a duration which is adjusted by the controller on the basis of the monitored breathing pattern of the patient; a feedback indicator which indicates to a patient whether the monitored breathing pattern is effective for inhaling drug-laden air or not a dose calculator which calculates the dose delivered to the patient; and an indicator which indicates to the patient when a desired dose has been delivered, whereby the apparatus is configured to deliver the full amount of the desired dose in at least 80% of treatments.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims priority under 35 U.SC. §120 as a Divisional ofU.S. patent application Ser. No. 10/203,337, filed Nov. 14, 2002, whichis the National Stage of International Application No. PCT/US01/04532,filed Feb. 12, 2001, which claims the priority under 35 U.S.C. §119(e)from U.S. Provisional Appl. No. 60/181,852 filed Feb. 11, 2000, all ofwhich are incorporated herein in whole by reference.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates to improved drug delivery apparatus, andto the use of improved drug formulations for delivery by the apparatus.

2. Description of the Related Art

A number of drugs have been used for the treatment of patients withrespiratory disorders. Antiproteinase inhibitors, such as Prolastin®,are being studied and used in the treatment of inflammatory lung diseaseand approved for use in congenital emphysema. Prostacylins/prostacylinanalogs, such as Iloprost, are used in the treatment of pulmonaryhypertension. Mucoactive drugs, such as Pulmozyme® (recombinant, humanDNase) and SuperVent®™ are used and studied in the treatment of patientswith cystic fibrosis lung disease. Gamma interferon is being studied foruse in the treatment of pulmonary fibrosis and tuberculosis.Immunosuppressants, such as cylosporine, are being studied for theprevention of lung organ rejection. The Interferons, specific monoclonalantibodies, directed against tumor-associated antigens, receptors oroncogene proteins, and adenovirus-directed gene therapeutics, are usedand studied as a treatment for various lung cancers.

Beta₂ adrenergic bronchodilators, such as Ventolin®, Albuterol® andSalbutamol®, are indicated for the prevention and relief ofbronchospasm. Corticosteroids, such as Budesonide®, are used in thetreatment of inflammatory lung and reactive airways disease such asasthma. Surfactants, such as Exosurf®, Survanta® and Surfaxin™, are usedto treat infant respiratory distress syndrome and are being studied astherapies in certain lung inflammatory diseases, such as chronicbronchitis and cystic fibrosis. Anti-infective agents [e.g.,antibacterial (e.g., tobramycin); antifungal (e.g., AmBiosome®); andantiviral (e.g., Synagis™, Virazole®, the Interferons and vaccines)] areused to control pulmonary infections, particularly in subjects who areat risk, such as children, the elderly and the immunocompromised and inpatients suffering for example with cystic fibrosis lung disease. Theselatter patients are prone to acute and chronic endobronchial infections,typically caused by the gram-negative bacterium, Pseudomonas aeruginosa.Pseudomonas infections are treated with the antimicrobial polypeptide,Colistin and the aminoglycoside antibiotic, Tobramycin.

WO 96/12471 discloses the use of an aminoglycoside formulation(Tobramycin) for aerosolisation. The formulation comprises from about200 mg to about 400 of aminoglycoside dissolved in about 5 ml ofsolution containing about 0.225% of sodium chloride. The formulation hasa pH of between about 5.5 to 6.5 and is administered by aerosolisation.This formulation suppresses and inhibits at least 95% of susceptiblebacteria in the endobronchial space of a patient suffering from theendobronchial infection.

Various drug delivery apparatus are suitable for delivering such drugsin atomised form. For example, a jet-type nebuliser is disclosed in WO96/12471 as being suitable for aerosolisation of the aminoglycosidesolution. This nebulises the formulation into an aerosol having aparticle size predominantly in the range of 1 to 5 μm. A limited numberof nebulisers are suitable for nebulising this formulation. Also,formulations of this kind have quite a large volume, and must bedelivered over more than one breath.

The suitable jet-type nebuliser is shown in FIG. 3 of WO 96/12471, andconsists of a case, a mouthpiece, a nebuliser cup covered with a cap, aventuri chamber, an air supply tube and a baffle. The liquid formulationis placed in the nebuliser cup, and an air supply tube is connected toit. The pressurised air passes from the cup into a jet nebuliser orificewhere an aerosol is created by shearing the liquid solution into smallthreads of liquid that shatter into small particles when they hit thebaffle. As a patient inhales through the mouthpiece, air is drawn inthrough air intake holes in the cap into the venturi chamber where itmixes with the aerosol and is carried to the patient.

All of the nebulisers disclosed are continuously operating nebuliserswhich generate an aerosol continuously.

In addition, WO 96/12471 mentions a study of the use of nebulisers todetermine the pharmacodynamics of aminoglycoside in the sputum ofpatients which is a measure of the efficacy of the aerosol delivery.Such jet nebulisers were found to be about 10% efficient under clinicalconditions, although the amount deposited and absorbed in the lungs isonly a fraction of that 10%. Thus, large quantities of the drug must beused if the required dosage of the formulation is to reach the patient.For this reason, the prior art document is directed to a formulationcomprising from about 200 mg to about 400 mg of aminoglycoside dissolvedin about 5 mls of solution. This is a large mass of drug to be deliveredto a patient, and it means that the treatment must be delivered over anumber of inhalations lasting maybe several minutes. An example of tento thirteen minutes to deliver 300 mgs is given. Single inhalationatomisers, as disclosed in WO 96/09085 and WO 96/13292, are limited to amaximum drug mass per inhalation of less than 10 mgs. Such atomisersare, therefore, not suitable for delivering antibiotics.

Other suitable nebulisers are mesh type nebulisers.

Some drugs, including antibiotics, give no direct feedback to thepatient on their effectiveness at the time of inhalation, unlike abronchodilator for asthmatics which has an immediate effect in easingthe patient's symptoms. Further, the inhalation of aerosols, even whenappropriately formulated for pH and tonicity may still cause bronchialconstriction and coughing in patients. As a result, the patient has noreal idea of how much of the drug has been delivered. He or she merelycontinues to inhale the atomised substance until there is none left.

In a recent study, the connection between the duty cycle in vitro andthe inhaled dose during domiciliary nebuliser use has been investigated.The effectiveness of domiciliary nebuliser therapy is determined by theadherence to a prescribed regimen, the deposition of the drug in theappropriate area of the lungs, and the breathing pattern duringnebulisation. The breathing pattern of patients was measured in thelaboratory, and from those measurements the patient's duty cycle wascalculated. The duty cycle is the proportion of the time the patientspends in inspiration and this normally falls in the range of 0.3 to0.5. If the patient is inhaling aerosol from a nebuliser, then theamount of aerosol that he or she inhales is directly proportional to hisduty cycle. This has been confirmed by measurement of the inhaled doseon a filter during testing, and also using lung scintigraphy.

When similar measurements are made during domiciliary nebuliser use, theduty cycle recorded is significantly less than that recorded in thelaboratory. This is because the nebuliser output is continuous andpatients interrupt their treatment to rest, talk, drink or as a resultof disease related symptoms such as coughing. This reduces the amount ofdrug inspired by the patient. In addition, using the duty cycle tomeasure dosage does not take account of whether or not the patient has agood inhalation method, nor whether the patient is adherent to thattreatment regimen, for example taking the number of treatmentsprescribed by their doctor. This makes it particularly difficult toassess why a patient does not respond to the treatment, because thedoctor does not know whether it is because the patient is not complyingwith the regimen prescribed, because the patient is not inhalingproperly from the delivery system, or because the drug is ineffective.It is quite clear from various studies that a very high proportion ofpatients are not adherent to their treatment regimen.

Clearly, if the domiciliary duty cycle is much less than the duty cyclemeasured in a laboratory, the patient is receiving significantly less ofthe prescribed drug. In addition, a poor inhalation method by thepatient and failure to comply with the regimen farther reduce the amountof drug received in the lungs of the patient. The percentage of thepredicted dose actually received by the lungs of the patient variesenormously. Typically, less than 10% of the initial volume of drugplaced in a nebuliser reaches a patient's lungs in domiciliary use.Thus, it is clear that something of the order of ten times as much ofthe drug is required to be atomised as actually reaches the patient'slungs.

A number of different types of apparatus for delivering a drug into thelungs of a patient are known. The pneumatic or jet-type nebuliser isparticularly effective in supplying an aerosolised drug for inhalation,but other types of nebulisers are available, such as the ultrasonic-typenebuliser in which the drug to be atomised is forced through a mesh by avibrating piezo-electric crystal whereupon the droplets passing throughthe mesh are entrained in the air being inhaled by the patient. The meshgauge determines the size of the droplets which enter the air stream.Alternatively, a dosimetric spacer can be used. When using a spacer, thedrug is introduced into the holding chamber of the spacer either inaerosolised form, or by loading the air within the holding chamber withthe drug in powdered form. The patient then breathes from the holdingchamber, thereby inhaling the drug-laden air. Such spacers areparticularly effective when treating children or elderly patients, andfor use with certain drugs. The drug is normally delivered over a numberof breaths. Of course, the concentration of the drug in each breathdecreases over time as a result of dilution caused by ambient airentering the holding chamber to replace air being inhaled by thepatient, and as a result of the deposition of the drug within thechamber.

SUMMARY OF THE INVENTION

According to a first aspect of the present invention, a drug deliveryapparatus comprises a drug delivery device for selectively deliveringdrug-laden air or air not laden with the drug; a sensor for monitoringthe breathing pattern of a patient, a controller arranged to control thedrug delivery device to deliver drug-laden air in pulses which beginwhen the patient is monitored by the sensor to begin inhalation, thepulses having a duration which is adjusted by the controller on thebasis of the monitored breathing pattern of the patient; a feedbackindicator which indicates to a patient whether the monitored breathingpattern is effective for inhaling drug-laden air or not a dosecalculator which calculates the dose delivered to the patient on abreath-by-breath basis; and an indicator which indicates to the patientwhen a desired dose has been delivered, whereby the apparatus isconfigured to deliver the full amount of the desired dose in at least80% of treatments. As a result of these features of the drug deliveryapparatus, the desired dosage is delivered in at least 80% oftreatments. This is a result of the combination of a number of factors,including the delivery of drug-laden air only in the part of theinhalation phase which reaches the lungs, and also as a result of thepatient receiving an indication as to whether or not he or she isinhaling properly. It is also important to indicate to the patient whenthe appropriate dose has been delivered. The delivery of the full amountof the dose in at least 90% of treatments, or preferably in at least 90%of treatments is a huge improvement over delivering apparatus which hashereto been used. This improvement offers a number of advantages sincealmost all of the drug which is delivered is delivered correctly to thecorrect part of the lungs. This means that considerably less of the drugformulation is required than with existing atomisers. This reduces thecost of the drug, and also shortens the amount of time in which deliverymust take place. It may require less than one third of the number ofbreaths to inhale the correct dose when the apparatus according to thepresent invention is used over prior art delivery apparatus. Inaddition, because the apparatus reacts to the patient in order tooptimise the length of the pulse in which drug-laden air is delivered,the apparatus is ideal for domiciliary use instead of use merely inhospital. Thus, considerable advantages are received by using thepresent invention.

It is preferred that the apparatus includes a data log for recordal ofinformation relating to each treatment, including the dose which wasdelivered. This also adds to the advantages of domiciliary of theapparatus since a doctor can later review the data from the data log tosee how well the patient, in fact, complied with the treatments, but interms of the number of treatments which the patient has taken, and thedose actually received during each of those treatments.

The drug delivery device may be any device which delivers the drug intothe lungs of a patient over multiple inhalations. For example, it may bedosimetric spacer including a receptacle defining a holding chamber, amesh-type atomiser, or a pneumatic-type atomiser.

Other advantageous features are recited in the dependent claims.

The use of such an aerosol delivery system, which only causesatomisation of the drug during inhalation, and adapts to the patient'sinhalation pattern significantly reduces the volume of drug requiredsince there is significantly less wastage because no aerosol isgenerated on exhalation. A particularly surprising effect of the use ofsuch a delivery device is that there is a substantial increase inpatients' compliance with the treatment regimen By compliance, it ismeant that patients adhere to the prescribed regimen by actually takingprescribed doses at the right time. It is believed that such a deliverysystem results in more than 90% of treatments being taken correctlyuntil the device signals that the patient has achieved the correcttreatment. Unexpectedly high levels of compliance result from thissystem, so the present invention gives a significant and unexpectedadvantage compared with other delivery systems. Whereas only about 10%of the volume of drug placed in a conventional nebuliser reaches apatient's lungs, and it is lower in the case of domiciliary use, thepresent invention means that the amount of drug placed in the nebuliserwill fall by approximately 50%. This will lead to significant reductionsin drug costs, and will also mean that it will take a much shorter timefor the required drug to be administered to a patient.

BRIEF DESCRIPTION OF THE DRAWINGS

Embodiments of the present invention are described below by way ofexample, and with reference to the drawings in which:

FIG. 1 is a schematic diagram of a dosimetric spacer according to thepresent invention;

FIGS. 2 and 3 are schematic diagram showing a second form of dosimetricspacer in which a piston is movable through the holding chamber;

FIG. 4 is a block diagram of a controller for controlling the operationof the second embodiment shown in FIGS. 2 and 3;

FIG. 5 is a graph showing a breathing pattern of a patient;

FIGS. 6 and 7 show the upper and lower parts of a nebuliser according toa further embodiment to the present invention;

FIG. 8 is a flow diagram of the operation of an atomiser of the typeshown in FIGS. 6 and 7;

FIG. 9 is a graph showing the predicted tidal volume cluttered againstthe measured tidal volume; and

FIG. 10 shows a two-part drug package for supply of the drug.

DETAILED DESCRIPTION OF THE EXEMPLARY EMBODIMENTS

Referring to FIG. 1, a housing 1 a defines a holding chamber 1 whichincludes an inlet 2 through which a liquid or dry powder drug passesinto the holding chamber from a source of droplets or particles, forexample, a multi-dose inhaler (MDI) 3. The MDI 3 releases the liquid orpowder drug in a cloud such that it loads the air with the drug. Asensor 4 is disposed between the MDI 3 and the holding chamber 1 whichdetects each actuation of the MDI 3. The sensor 4 also detects the rateat which air or other gas enters the holding chamber 1 via the inlet 2.

The holding chamber 1 also includes an outlet 5 to which a mouthpiece 6is attached. A patient inhales from the mouthpiece 6 drawing air or gasladen with the drug from the holding chamber. This causes ambient air orgas to be drawn into the holding chamber 1 via the inlet 2. The rate offlow of air through the inlet 2 is detected by the sensor 4.

A first valve 7 a is disposed between the outlet 5 and the mouthpiece 6through which drug-laden air passes when the patient inhales. A secondvalve 7 b, is disposed in the mouthpiece 6 which permits exhaled air tobe vented to atmosphere. A controller (described in more detail below inconnection with FIG. 4) operates to control both the first and secondvalves (7 a, 7 b). The first valve must be closed during exhalation sothat exhaled air does not enter the holding chamber 1. A second sensor 8is located in the mouthpiece in order to monitor the breathing patternof the patient. The controller operates the first and second valves 7 a,7 b on the basis of the monitored breathing pattern. When the patientbegins to inhale, the second sensor 8 detects this and the controlleroperates the valves such that the first valve 7 a is open and the secondvalve 7 b is closed in order that the patient inhales drug-laden airfrom the holding chamber 1. Once the controller decides that no more ofthe drug-laden air is to be delivered to the patient, or the patientstops inhaling, the first valve 7 a is closed and the second valve 7 bis opened such that the patient finishes any remainder of the inhalationwith ambient air which enters the mouthpiece via the second valve 7 b,and exhales through the mouthpiece such that the exhaled air is ventedto atmosphere via the second valve 7 b and does not enter the holdingchamber 1. The controller allows inhalation of drug-laden air from theholding chamber 1 in pulses, the duration of which are adjustedaccording to the monitored breathing pattern of the patient. Thecontroller also analyses the breathing pattern of the patient to ensurethat inhalation is suitable for delivering the pulse of drug-laden air.If it is too weak, or too unsteady, the pulse of drug-laden air will notbe delivered, or will stop early.

Two indicators 16 and 17 are included in this spacer. The firstindicator 16 is a patient feedback indicator which indicates to apatient whether or not suitable inhalation is taking place. In thisembodiment, the feedback 16 is a vibrator unit which vibrates gentlyduring inhalation while drug-laden air is delivered. As soon as thefirst valve 7 a closes and the second valve 7 b opens, the feedbackindicator 16 will turn off. Also, if the patient does not inhaleproperly, the feedback indicator 16 will either stop vibrating or willnot start vibrating. Thus, a patient will quickly learn how to inhalecorrectly when using the spacer. The feedback indicator couldalternatively be an audible indicator emitting, perhaps, a hum whiledrug-laden air is being delivered, or a visible indicator such as an LEDwhich lights when drug-laden air is delivered.

The second indicator 17 indicates when the patient has received a fulldose of the drug, and when treatment has ended. This could be an audibleindicator such as a small speaker emitting a tone, or a visualindicator, such as an LED. Of course, if appropriate, the feedbackindicator 16 and the second indicator 17 could be combined into a singleindicator, preferably a vibrator or a source of an audible signal.

Once the drug has been released into the holding chamber 1, itsconcentration decreases, firstly as a result of deposition as the drugsettles on the walls and base of the holding chamber due to gravity andelectrostatic forces between the housing 1 a and the drug, and secondlyas a result of dilution caused by air entering the holding chamber viainlet 2 to replace drug-laden air inhaled by the patient.

Calculations must be carried out by a dose calculator (not shown) inorder to determine the dose of the drug which has actually beendelivered to the patient. Details of these calculations are made in ourearlier joint patent application published under WO 96/13294, thecontents of which are hereby imported into this specification in itsentirety. In summary, the dose calculation is carried out on abreath-by-breath basis, the amount of the drug delivered in a breathbeing added to the amount delivered in each previous breath until thedesired dose has been delivered. At that stage, the dose calculatorcauses the second indicator 17 to indicate that treatment has ended, andthe controller no longer allows delivery of the drug-laden air. Inaddition, the dose calculator includes a formulation input since thespacer can be used for various different drug formulations. Theformulation input could be in the form of buttons on the spacer by whichthe drug formulation being used may be selected. More details of thedose calculator are described in connection with FIG. 4.

A further spacer embodiment is shown in FIG. 2. This spacer is arrangedto operate specifically in conjunction with dry powder inhalers (DPI's).DPI's are normally actuated by the patient's inspiratory flow. They arenot suitable for patients with a very low inspiratory flow since the DPIis unlikely to be triggered reliably. DPI's release the drug in the formof a fine powder which is inhaled by a patient into his or her lungs. Aswith conventional MDI's conventional DPI's suffer from the disadvantagethat much of a given dose impacts on the back of a patient's throat.Referring to FIGS. 2 and 3, a housing 1 a defines a holding chamber 1,and includes a first port 9 which is used both to load and empty theholding chamber 1. The spacer also includes a piston 10 movable withinthe chamber 1. As the piston 10 is drawn back, air or gas is sucked intothe holding chamber 1 via the first port 9, and air trapped behind thepiston escapes through a second port 11.

In use, and as shown in FIG. 2, the piston 10 is pulled back drawing airor gas into the holding chamber 1 through the first port 9. Beforereaching the first port 9, the air or gas passes through a dry powderinhaler 13 which releases the drug into the air or gas, and over asensor 4. The piston 10 is fixed in the retracted position. The patientthen removes the DPI 13 and replaces it with a mouthpiece 6 as shown inFIG. 3. The patient then inhales via the mouthpiece 6 and the air or gasloaded with the drug is sucked from the holding chamber passing throughthe port 9, over the sensor 4 and through the mouthpiece 6. The sensor 4detects this airflow.

The piston 10 returns across the holding chamber 1 as the patientinhales, and is arranged to move only in the direction of emptying theholding chamber 1 to prevent dilution. To permit the patient to exhale,a one-way valve 14 is disposed in the mouthpiece 6. The mouthpiece 6also includes a second valve 15 which is controlled by a controller(described below) such that when drug-laden air is not delivered duringinhalation of the patient, the valve 15 is opened to allow ambient airto enter the mouthpiece before inhalation by the patient. As will beexplained below, this allows the drug to be delivered in pulses. Thus,the controller operates the valve 15 on the basis of informationreceived from the sensor 4 which monitors the breathing pattern of thepatient. When it detects a patient inhaling correctly, the controllercloses valve 15 so that the patient inhales from the holding chamber 1.Once the pulse of drug for that breath has been received, the valve 15will open again so that ambient air and not drug-laden air is receivedby the patient. The duration of the pulse is determined by thecontroller to optimise the delivery of the drug. During exhalation, theexhaled air is exhausted through the one-way valve 14. It will be notedthat, since no ambient air enters the holding chamber during inhalation,any reduction in concentration of the drug within the holding chamber isa result of deposition of the drug within the chamber.

As in FIG. 1, two indicators 16 and 17 are present. A patient feedbackindicator 16 indicates to a patient whether or not suitable inhalationis taking place, and the second indicator 17 indicates when a patienthas received the full dose, and that treatment has ended.

Calculation of the dose given to the patient is now described inconnection with the embodiment shown in FIGS. 2 and 3. The patientfirstly connects the DPI 13 to the port 9. The piston 10 is pulled backdrawing air into the holding chamber 1 via the DPI 13 and the port 9 sothat the holding chamber is charged with the drug. The sensor 4, whichmight be a microphone or a pressure detector, detects this introductionof the drug into the holding chamber 1 and produces a signal. The dosecalculator (not shown) receives the signal from the sensor 4 and startsa clock (not shown). The patient then removes the DPI from the port 9and replaces it with a mouthpiece (FIG. 3). The patient inhales throughthe mouthpiece, and the air flows past the sensor 4. The dose calculatorcalculates the amount of the drug delivered to the patient veryfrequently, typically every one hundredth of a second. The concentrationof the drug within the holding chamber 1 is continuously calculated totake account of the deposition of the drug on the walls of the holdingchamber 1 over time. A memory contains a data look-up table which givesthe concentration of the drug in the chamber 1 at a time after itsintroduction. The dose of drug inhaled is then calculated by multiplyingthe volume of air sensed by the sensor 4 by the concentration of thedrug at that time. The dose calculated during this one hundredth of asecond sample period is then added to the dose calculated incalculations for previous sample periods. The calculation could,alternatively be calculated on a breath-by-breath basis. Once thecumulative total dose reaches a predetermined level, an indication ismade to the patient that the full dose has been given via the secondindicator 17.

FIG. 4, shows a block diagram of the controller 24 for the spacer shownin FIGS. 2 and 3, but which would also be suitable for the spacer shownin FIG. 1. The controller 24 includes a processor 25 powered by a powersupply 34. The sensor 4 sends signals to the processor 25 via anamplifier 32 to indicate when the drug is being introduced into theholding chamber 1, and the rate of inhalation of the patient. Theprocessor 25 calculates the dose given to the patient on the basis of aprogram 29, a memory 30 containing look-up data 31, and a clock 27.Before treatment starts, it is necessary to enter the drug formulationwhich is being delivered. One way of doing this is for the apparatus toinclude a drug formulation input 26 which is in the form of buttons onthe apparatus. The apparatus may be suitable for delivering any of anumber of drugs to a patient and pressing a button allows the processor25 to take account of whatever formulation is being used. Informationregarding drug formulations is stored in the memory 30. The processor 25will normally calculate the amount of drug delivered to a patient on abreath-by-breath basis, adding the dose detected to have been deliveredin one breath to the amount delivered in each preceding breath. This maybe done by sampling the air flow on a regular basis during inhalation.Once the processor has calculated that the predetermined dose has beengiven, a signal is output to the end indicator 35, and treatment isstopped such that the patient can only inhale ambient air through themouthpiece, and not medication-laden air.

The processor 25 also analyses the breathing pattern such that, ifduring inhalation, the patient is breathing correctly, the patientfeedback indicator 16 is caused to indicate to the patient that correctinhalation is taking place. Correct inhalation might be considered totake place where the inhalation is above a certain strength, or is ofsuitable stability. In analysing the breathing pattern, the processor 25also generates a pulse during which drug delivery takes place. The pulsewill not take place, or will be terminated early, if the breathingpattern is not considered to be suitable. Thus, the patient feedbackindicator 16 can be caused to indicate to the patient only when correctinhalation is taking place during delivery of the drug. If inhalationbecomes unsuitable for drug delivery during a pulse, the pulse will beterminated early, and the patient feedback indicator 16 will no longerindicate to the patient that correct inhalation is taking place.

In order to deliver the drug in the most effective manner, the processor25 analyses each breath, and on the basis of the previous breath orbreaths, controls the valves so as to deliver the drug in pulses intoonly a part of the inhalation phase of the patient. The processorincludes a pulse generator (not shown) which generates pulses duringwhich the drug is delivered. The pulse generator controls when eachpulse begins and its duration. For example, the pulse of drug deliverymay occur in the first 50% of the inhalation phase of a patient.However, the duration of the patient's inhalation phase may vary fromtreatment to treatment, and even during a single treatment. Thus, theprocessor 25 must adapt to this change. For example, if the processor isgenerating pulses of drug delivery which correspond to the first 50% ofthe inhalation phase, it will need to determine the length of theprevious breath or a number of the previous breaths using the clock 27.

On the subsequent breath, the pulse length generator of the processor 25can generate a pulse as soon as it receives a signal from the sensor 4that the patient has begun to inhale. The length of the pulse will be50% of the length of the preceding inhalation phase, or 50% of anaverage of for example, the preceding three inhalation phases. If thepatient fails to inhale correctly, the processor 25 will stop the pulseand indicate to the patient that his or her inhalation is not suitable.The processor 25 controls the valves as described in relation to FIGS. 1to 3.

Alternatively, the pulse length may be increased to more than 50%, and adescription of a further arrangement in which the pulse length ismaximised is described in a later embodiment of this invention. Such anarrangement can be applied to the dosimetric spacer.

The memory 30 can also be utilised to record the dose delivered by theapparatus during each treatment. The processor 25 acts as a dosecalculator during each treatment to calculate the dose delivered on abreath-by-breath basis. At the end of a treatment, whether as a resultof the full dose being delivered, or as a result of the patient stoppingtreatment prior to a full dose being delivered, the dose actuallydelivered is recorded in the memory 30 so that at a later date, a doctoror other person can review the dose received by the patient so as to seewhether or not that patient was compliant with the treatments. If, forexample, the patient has not responded to treatment, it is possible fora doctor to tell whether or not compliance with the regimen has beenadhered to, and if so, a different treatment may be prescribed. Thus,the memory 30 also constitutes a data log of treatments. It willnormally also record the time when each treatment was administered, andmight even include information on the patient breathing pattern ifrequired.

Reference has been made above to look up tables which give data on howconcentration of the drug decreases in time, and how concentration ofthe drug decreases by dilution caused by inhalation of known volumes.The data in the look-up tables must be gathered by experiment. Forexample, when the data for decrease in concentration of the drug withtime is gathered, a known amount of the drug is introduced into theholding chamber, and the air in the holding chamber 1 is then expelledafter a time into the filter paper. The expelled drug is then weighed.This experiment is repeated for different time periods to establish thenecessary data. The variation of concentration with time profile islikely to be different for different drugs. Therefore the apparatus musthave the correct profile programmed in.

A nebuliser according to the present invention will now be described. Inorder to appreciate the invention, reference is made to FIG. 5 in whichthe inhalation pattern of a patient is shown over time. It will beappreciated that breathing patterns are not very regular, and that somebreaths are deeper than others.

FIGS. 6 and 7 of this application show a nebuliser. Referring to FIG. 6,a mouthpiece 101 is shown through which a patient inhales in thedirection of arrow 102. Below the mouthpiece 101 is a removableatomising section 103 which, in turn, rests on a base 104.

The base 104 is shown in more detail in FIG. 7. Referring to FIG. 7, thebase 104 includes an inlet 105 through which air is supplied underpressure from a compressor (not shown). The pressurized air is led via atube 106 to a manifold 107 which controls the flow of pressurized air toan air outlet 108 which directs air into the atomising section 103 shownin FIG. 6. The base 104 also includes a pressure sensor 109 whichdetects the pressure within the atomising section 103 via a port 110.

Referring again to FIG. 6, air under pressure passes through the airoutlet 108 of the base 104 and is conducted through a tubular post 111to an atomiser nozzle 112 out of which the air issues under pressure. Adeflector 113 is located in the path of the pressurised air issuing fromthe nozzle 112 so that the pressurized air is deflected laterally so asto pass beneath a baffle 114. The passage of the pressurized air acrossthe top of the tubular post 111 causes a drug 115 to be drawn up betweenthe outer surface of the tubular post 111 and the inner surface of asleeve 116 which surrounds the tubular post 111. The drug 115 isatomised in the stream of air, and carried away in the stream of airbelow the rim of the baffle 114 and up through the mouthpiece 101 to apatient.

The pressure sensor 109 in the base 104 monitors the breathing patternof a patient, and on the basis of the breathing pattern, the manifold107 is controlled to supply pressurized air to the atomising section 103in pulses only during the first 50% of an inhalation phase so that drugdelivery only occurs during that pulse.

This invention applies to atomisers which generate drug delivery pulses.The invention is not, however, limited to the exact atomiser describedabove, but may be applied to other atomisers. For convenience, thedescription below of the present invention will refer to components ofthe device shown in FIGS. 6 and 7, but it can be applied to otheratomisers, such as other designs of jet nebulisers, ultrasonic atomisersand pressure mesh atomisers.

Jet nebulisers are of two kinds, these being air-jet nebulisers andliquid jet nebulisers. An example of an air-jet nebuliser, which uses asource of compressed air to nebulise a liquid, is disclosed in EP0627266 (Medic-Aid Limited), the content of which is incorporated hereinin its entirety by reference. An example of a liquid-jet nebuliser,which drives a liquid through one or more nozzle outlets to produce aspray of fine droplets is disclosed in WO 94/07607 (Boehringer IngelheimInternational GmbH et al), the content of which is incorporated hereinin its entirety by reference.

Ultrasonic nebulisers nebulise a liquid drug using ultrasonic wavesusually generated with an oscillating piezo-electric element and takemany forms. These include nebulisers 1) where liquid is in directcontact with the piezo-electric element, 2) where there is an amplifyinginterface, typically an enclosed fluid, between the piezo-electricelement and the liquid, and 3) where the piezo-electric element vibratesa mesh from which an aerosol is generated. Examples of ultrasonicnebulisers are disclosed in U.S. Pat. No. 4,533,082 (Maehara et al) andU.S. Pat. No. 5,261,601 (Ross et al), the contents of which areincorporated herein by reference. The nebulisers described in thosedocuments include a housing that has a reservoir which holds a quantityof liquid to be dispensed, which housing has a perforated membrane incontact with the reservoir and an ultrasonic vibrator connected to thehousing to vibrate the perforated membrane. Another example of anultrasonic nebuliser is described in WO 97/29851 (Fluid PropulsionTechnologies, Inc), the contents of which are incorporated herein byreference. An example of a pressure mesh nebuliser, which may or may notinclude a piezo-electric element, is disclosed in WO 96/13292 (AradigmCorporation), the contents of which are also incorporated herein byreference.

As mentioned above, all of the above types of nebuliser can be used toatomise the drug in pulses. This means that atomisation and drugdelivery can be switched on and off. The pulses can be controlled sothat atomisation only occurs during a part of the breathing pattern of apatient in which it will be of benefit. With reference to the deviceshown in FIGS. 6 and 7, the sensor 109 is extremely important in thatthis measures the breathing pattern of the patient. A controller (notshown) receives the breathing pattern information from the sensor 109and analyses the breathing pattern of the patient. It will calculate thelength of time in which the patient inhales, and on the basis of thatinformation will control the manifold 107 such that atomisation onlyoccurs in a pulse of drug delivery during a part of the inhalation ofthe patient.

The controller may be of the same form as that disclosed in FIG. 4. Inthat arrangement, the controller includes a processor 25 which carriesout a number of functions, acting as generator of pulses of drugdelivery, a dose calculator for calculating the dose delivered on abreath-by-breath basis, and a breathing pattern analyser for analysingthe breathing pattern of a patient and, determining whether or not thepatient is breathing correctly so that a feedback indicator can be usedto indicate to the patient whether or not correct inhalation is takingplace. In addition, the processor can take account of differentformulations provided that the apparatus includes an input for enteringthe drug formulation being used. The controller can also log informationconcerning the treatments, such as the dose delivered, when eachtreatment was delivered, and information on the breathing pattern of thepatient.

For example, a good arrangement is to generate a pulse of drug deliveryonly in the first 50% of the inhalation of the patient. Since theduration of inhalation of a patient varies between treatments, and alsowithin a single treatment, it is necessary to monitor the duration ofinhalation over one or more breaths so that the average duration ofinhalation can be calculated in order that the pulse length can bedetermined for the next breath. Once determined by the controller, assoon as the controller receives an indication from the sensor 109 thatinhalation has started, it will generate a pulse of drug delivery equalto half of the average duration of inhalation of the patient. Inaddition, the inhalation of the patient is analysed to ensure that it issuitable for delivering the drug. If the breath is too weak or isinterrupted, or is very uneven in strength, the pulse of drug deliverywill not begin, or will be terminated early. To assist the patient inknowing what is a suitable breath and what is not, the nebuliserincludes a patient feedback indicator (not shown) which indicates to thepatient either that the breath is suitable, or that it is unsuitable.This may be a visual or audible indicator, or even a small vibrator. Itis preferred that the nebuliser indicates when a patient is inhalingcorrectly, and the signal received by the patient could coincide withthe pulse of atomisation. In this way, if the inhalation is notsuitable, the pulse of atomisation is stopped, and the indication thatthe patient is inhaling correctly will also be stopped.

An end indicator (not shown) is also included which indicates to thepatient when the full dose has been dispensed. To do this, the atomiseralso includes a dose calculator which calculates the amount of the drugreceived by the patient on a breath-by-breath basis. The output of thedevice will be known through experimentation so that the total length ofthe pulses can be multiplied by the output rate of the nebuliser to givethe total dose received by the patient. Once the dose calculator hasdetermined that the full dose has been delivered, the end indicatorindicates to the patient either audibly or visibly that treatment hasended. The controller will not then generate any further pulses for thattreatment.

Extending the proportion of the inhalation of the patient in whichatomisation takes place above 50% results in the patient receiving theirtreatment faster since it will take fewer breaths to deliver therequired volume of medication. However, to avoid wastage of themedication which is atomised in the end volume of patient's inspiratoryvolume, the pulse of atomisation must be stopped before the end volumeis reached. The end volume is the volume of air inhaled by a patient atthe end of the inspiratory volume which remains in the upper airways(the mouth and trachea) and does not enter into the lower parts of thelungs. Any drug which is atomised into the end volume is wasted when thepatient exhales, together with any atomised drug left in the nebuliser,since it does not reach the lungs.

The end volume is the volume of the patient's upper airway, and isproportional to the size of the patient. Clearly, the end volume willvary as a percentage of the inspiratory tidal volume since the tidalvolume changes significantly depending on the type and extent of therespiratory disease suffered by the patient. The optimum duration of anatomisation pulse would, therefore, be from the start of inhalation upto the point during inspiration when the volume remaining to be inspiredequals the end volume. Atomisation would then be stopped and theremaining end volume would clear the atomised medication from the deviceand the upper airways of the patient and into the lungs. Thus, thepercentage of inspiration in which atomised medication is delivered ismaximised, thereby minimising treatment time and still avoiding wastageof medication. The length of the atomisation pulse is dependent upon thepatient's inspiratory tidal volume. The nebuliser must therefore measurethe patient's tidal volume, preferably on a breath by breath basis so asto calculate, for example from the previous three breaths, an averageinhalation volume for the next breath. Thus, the atomisation pulse timewill be calculated as follows:

${{Pulse}\mspace{14mu}{time}} = {{mean}\mspace{14mu}{inspiratory}\mspace{14mu}{time} \times \frac{( {{{mean}\mspace{14mu}{tidal}\mspace{14mu}{volume}} - {{end}\mspace{14mu}{volume}}} )}{{mean}\mspace{14mu}{tidal}\mspace{14mu}{volume}}}$

A timer is included in the nebuliser connected to the pressure sensor109 (shown in FIG. 7) in order to measure the duration of inspiration.Storage means are also included in the nebuliser in which an estimate ofthe end volume of a particular patient is stored. Since this figure is aconstant value for a particular patient, this can be entered at thebeginning of a course of treatment, and is estimated on the basis of thesize of the patient. The nebuliser includes a means for measuring thetidal volume of a patient. According to one form of the invention, thepatient's inspiratory flow is monitored continuously, typically everyten milliseconds, and this is integrated over the inspiratory duration.Another, simpler, way of measuring the tidal volume of a patient isdescribed later in this specification.

The nebuliser also includes means for calculating the atomisation pulsetime on the basis of the duration of inspiration, the tidal volume andthe end volume. The calculation means carries out the calculationoutlined above.

In view of the fact that the nebuliser adapts to the breathing patternof a patient, when the patient starts breathing, no atomisation takesplace during the first three breaths. Those first three breaths are usedto analyse the breathing pattern of the patient. The flow rate of thefirst three breaths are measured, and from this, the duration of theinhalation phase of the first three breaths are calculated, and anaverage found. The average duration of inhalation is then used in thecalculation to determine the pulse length of atomisation during thefourth breath. In addition, as the patient continues to breathe in andout, the previous three breathing patterns are measured and used tocalculate the next pulse duration. Thus, if a patient's breathingpattern improves during treatment, the nebuliser will adapt to thischange in order to optimise the dose administered during each breath.

Referring now to FIG. 8, the steps taken by the nebuliser, and by thepatient are described. The first operation, box 130 represents thepatient starting to inhale. The timer records the time at whichinhalation starts as shown in box 131, and during inhalation, acalculation is performed to predict the tidal volume of the patient asshown in box 133. This step will be described in more detail later in aspecification, but it will be noted that the calculation requires datato be included in the calculation including the inhalation time and peakflow as an average from the last three breaths, as shown in box 132. Thepulse time is then calculated as shown in box 134, and the pulse time isadjusted, as shown in box 135 in the event that the pulse length wouldexhaust an accumulator from which is pressurised air is supplied to thenebuliser. The pulse of atomisation occurs during inhalation, and afterit has stopped, a calculation is carried out to determine what dose hasbeen atomised. At the end of the breath as shown in box 138, details ofthe peak flow of the patient inhalation, and the duration of inhalationare recorded so that calculations determining pulse length may be madefor subsequent breaths. This is shown in box 139.

Reference is made above to the simpler prediction of tidal volume. Aswill be appreciated, measuring tidal volume by integrating measured flowrate over the time of inspiration requires considerable processing powerand is relatively expensive. A simpler method of determining the tidalvolume is proposed which requires much simpler calculations and muchsimpler measurements to be made for use in such a calculation. To carryout the measurement, the nebuliser includes a peak flow detector fordetecting the peak flow rate of inspiration.

The calculated, or predicted tidal volume is derived from the peak flowmeasured by the peak flow detector, and the duration of inspirationmeasured by the timer. The tidal volume calculation means carries outthe following calculation:

${{Predicted}\mspace{14mu}{tidal}\mspace{14mu}{volume}} = {C \times {Mean}\mspace{14mu}{Peak}\mspace{14mu}{Flow} \times \frac{{Inspiratory}\mspace{14mu}{Time}}{60}}$

C is a constant and it is found that C=0.7

FIG. 9 is a graph of the predicted tidal volume against measured tidalvolume. Each point on the graph represents a patient whose tidal volumehas been measured by a complex tidal volume calculation by integrationof the patient's inspiratory flow over the duration of inhalation, andthe predicted tidal volume according to the new, simpler method ofcalculation. It will be seen that the predicted tidal volumes areextremely accurate, and so the predicted tidal volume may be included inthe calculation of atomisation pulse time.

The use of this invention provides a particularly effective therapy whenmultiple inhalations are required, as is usually the case for systemicdrug delivery via the lung alveoli or local drug delivery to the lungfor respiratory disease, as in the case of the use of anti-infectivedrugs. It significantly reduces the volume of drug required becausethere is reduced wastage as no aerosol is generated on exhalation andlost to the environment, but only on the initial phase of inhalation.Also, such an atomiser informs the patient when treatment is completeand the correct dose is received. This prevents the patient fromreceiving too much of the medication or an overdose, and ensures thatenough of the drug is received for proper therapeutic effect. Withantibiotic drugs, for example, where such large quantities are requiredto be administered, it has been unexpectedly found in tests that thereis a significant increase in a patient's compliance with the treatmentregimen, at least to 80% of treatments and normally to at least 90% oftreatments.

FIG. 10 shows a drug package suitable for storage of most aerosol drugproducts, including anti-infectives and proteinaceous material, andtheir administration into the drug delivery apparatus. Many aerosol drugproducts, when in solution, have a limited stability and shelf-life.Consequently, such products, as stated herein, are supplied in a driedform, such as a powder, crystalline, micronized or lyophilized solidmaterial, which must be reconstituted prior to inhalation. Other aerosoldrug products in their final liquid formulation may have a limitedshelf-life as well. Consequently, such products require theiringredients to be admixed at the time of inhalation. FIG. 10 shows anexample of a drug package suitable for supplying aerosol drug productsthat require packaging in a dried form or require their liquidingredients to be separated until use. Those skilled in the art willappreciate that FIG. 10 shows a drug package that can integrate with adrug delivery device to enable the proper and accurate administration ofa reconstituted dried aerosol solution or even an aerosol drug packagedtherein as two separate liquid components. The package includes a body201 from which extends a tube 202. From the opposite side of the body201 extends a piston 203, which may be pushed through the body 201 andinto the tube 202. For this reason, the piston 203 includes a knob 204so that the fingers of a person can push the piston 203 inwardly bysqueezing the knob and a flange of the body 201 together.

The tube 202 is divided into a first chamber 205 and a second chamber206 separated by a stopper 207. The end of the tube 202 furthest fromthe body 201 is closed by a closure 208. The end of the tube 202 isdesigned to integrate with the drug delivery apparatus at either themouthpiece, baffle, medication chamber, or other suitable location so asto provide a direct connection for the liquid or reconstituted aerosoldrug product to enter the drug delivery apparatus. The first chamber 205contains the solid drug product and the second chamber 206 contains adiluent/solvent in which the dry/dried product is soluble.Alternatively, the first chamber 205 contains a liquid constituent ofdrug product and the second chamber 206 contains the other miscibleliquid constituent. The stopper (207) keeps the two apart until mixingis required.

The piston 203 is threaded towards the end closest to the body 201 andthe body 201 includes internal threads which engage with the threads 209of the piston 203.

In use the piston 203 is turned with respect to the body 201 so that thepiston pushes the material from the second chamber 206 past the stopper207 into the first chamber 205 where mixing of either the solid andliquid or liquid and liquid components of the aerosol drug product takesplace. The piston is then pushed through the body 201 such that theliquid drug product is expelled from the tube 202 at the end whichcontains the closure and attachment (integration) with the drug deliveryapparatus or atomizer. The liquid aerosol product is thus expelleddirectly and accurately into the atomizer.

It can also be appreciated by one skilled in the art that the drugpackage suitable for storage of most aerosol drug products and theirexpellsion into the atomizer, may be designed with only a singlechamber, where the first chamber 205 and second chamber 206 are notseparated by a stopper 207. This one part drug package would be suitablefor use with liquid aerosol drug products that can be packaged in theirfinal formulation, i.e., the formulation that is inhaled and dispenseddirectly and accurately into the atomizer.

In order to describe the advantageous effect of the apparatus, examplesof the drugs which may be used will now be described. The drugsconcerned require treatment over multiple breaths due to the volume ofdrug delivered. Solution based formulations require between 0.1 and 0.5ml to be delivered, and powder-based drugs between 1 and 5 mgs. Most ofsuch drugs are used for prophylactic treatment and do not give anydirect feedback in terms of benefit at the time of treatment nornegative feedback such as coughing.

In the following, it should be understood that the “lung dose” is theamount of a drug which reaches the lungs, and that to achieve the lungdose, it is necessary to deliver more than that since some of the drugwill not reach the lungs.

An important drug which is delivered to the lungs is Tobramycin. Atypical treatment of Tobramycin requires the delivery of 30 mgs to thelungs. A typical nebuliser delivers about 10% to the lungs which meansthat 300 mgs of Tobramycin must be nebulised. 300 mgs would normally bedissolved in 5 mls of 0.225% NaCl having a pH of 5.5 to 6.5. Thus, theconcentration is 60 mg/ml. However, the use of the present inventionallows considerably less of the drug to be used. Since deliveryefficiency is at least 80%, if a dose of 15 mgs is required to reach thelungs, only 19 mgs needs to be delivered. The formulation can be thesame as is described above in connection with existing nebulisers, butthe amount of the drug used is much less. Of course, in addition to theamount of the drug which is dispensed, a delivery apparatus will have adead volume which is residual and remains in the delivery device even ifdelivery continues. For example, with some pneumatic or jet-typenebulisers, the dead volume may be as much as 0.8 ml. However, amesh-type atomiser could have a dead volume of at little as 0.1 ml.Thus, the amount of the drug which is actually placed in the drugdelivery device may be 1.01 mls for the jet-type nebuliser (0.8 ml deadvolume+0.21 ml for delivery), or 0.42 ml for the mesh-type atomiser (0.1ml dead volume+0.32 ml for delivery). Of course, other types of drugdelivery device will have different dead volumes, and so the actualamount of the drug supplied for those devices will be different.

To provide effective control of one of the main infective lung organisms“Pseudomonas aeriginosa” in cystic fibrosis patients the concentrationof Tobramycin in the lung fluid must exceed the minimal inhibitoryconcentration (MIC) for the organism to be eliminated. For Tobramycinthe MIC level is typically required to be >16 μg/ml for 90% oforganisms, and the MIC concentration should be maintained at this levelfor 120 minutes.

To compare the performance of a conventional nebulizer and a highcompliance system according to this invention using Tobramycin 8patients received either 300 mg/5 ml via conventional nebulizer or 30 mgdelivered dose via the high compliance system. The mean sputumtobramycin concentrations at 2 hours were 128 μg/g for the conventionalnebulizer and 98 μg/g for the high compliance system. This study mayindicate that an even lower dose may be acceptable to achieve the MIClevel when delivered with a high compliance system such as disclosed inthis invention, in the range 5-30 mg Tobramycin.

Tobramycin is a stable drug and can be packaged as a unit dose solutionin a one-part package as described above in connection with a modifiedFIG. 10 or in a single glass or plastic unit dose vial.

If the drug Colistin is used (colistin sulphomethate) then the maximumdaily dose is 6 million units in three treatments. This is an equivalentlung dose of 600,000 U per day, but with the present inventiondelivering 300,000 U per day at an efficiency of over 80% allows only375,000 U to be delivered by the atomiser per day over two treatments of187,000 U per treatment. Thus, a very significant reduction in theamount of the drug is achieved. Four examples of the drug formulationfor Colistin are described below. In the first formulation, one millionunits of Colistin is dissolved in two mls of 0.9% NaCl. In the second,the Colistin is dissolved in a two mls solution made up from 0.75 ml of0.9% NaCl and 1.275 ml of water.

Alternatively, the formulation can include an additional bronchialdilator such that the Colistin is dissolved with 2.5 mgs of salbutamolin 2.5 mls of 0.9% NaCl, or alternatively with 2.5 mgs of salbutamoldissolved in 0.75 mls of 0.9% NaCl plus 1.275 mls of water. Finally, theColistin can be dissolved in a solution including 2.5 mg of DNase in 2.5mls of 0.9% NaCl. Since Colistin is not stable in solution, it issupplied as a powder which must be pre-mixed with a dilutant eithersupplied in a different vial, or in a two-part package, as describedabove in connection with FIG. 10. In the present application, the actualvolume of the Colistin formulation required to be placed in the drugdelivery apparatus may be 0.48 ml for a mesh atomiser, or 1.18 mls for ajet nebuliser, much less than in conventional nebulisers. Of course,other drug delivery apparatus will require different volumes accordingto their dead volume.

Another drug which can be delivered in the same way with similaradvantages is DNase. The required lung dose in a normal nebuliser is0.25 mgs. 2.5 mgs of DNase in 2.5 mls 0.9% NaCl is required in normal(conventional) nebulisers. However, in the present invention a lung doseof 0.125 mg delivered with 80% efficiency requires a dose of only 0.156mg, much less than in conventional nebulisers. The high efficiency isthe result of a particle size of the drug being within a narrow range ofsizes, about 3 microns in diameter. That way, 80% of the delivered drugreaches the lungs and stays there. Only 20% loss occurs due to impactionand exhalation.

Depending on the dead volume, the amount of drug supplied for a jetnebuliser may be 1.06 mls, and for a mesh atomiser 0.26 ml. Other drugdelivery apparatus will require different volumes depending on theirdead volume.

Approximately 38% of patients show a greater than 10% change in FEV₁over baseline when starting rhDNase therapy. Some patients may notrespond to inhaled therapies due to poor nebulizer techniques such asnose breathing, talking, coughing, resulting in poor inhalationcompliance.

A study to assesses the response to rhDNase delivered by a systemaccording to this invention in patients who have previously failed torespond to therapy with conventional nebulizer devices.

Eight Adult CF patients who had previously failed to respond to rhDNasetherapy (mean response to therapy 4.17% change in FEV₁) used aerosolizedrhDNase delivered for 10 days using 0.25 ml/0.25 mg of the formulation.the device. Mean change in FEV₁ was 11.51%.

This result shows that in CF patients who have previously failed torespond to inhaled therapies, have an improved response with a highcompliance delivery system, compared to their conventional nebulizer.This study may indicate that an even lower dose may be acceptable whendelivered with a high compliance system such as disclosed in thisinvention, in the range 0.06/0.25 mg rhDNase.

A further suitable drug is A1AT (Alpha 1 Antitrypsin) for which the lungdose for a conventional nebuliser is typically 20 mgs requiringnebulisation of some 200 mg of the drug in 4 ml of 0.9% NaCl. Because ofthe delivery efficiency of the delivery device according to the presentinvention, a lung dose of 10 mgs is required with the nebuliserdelivering 12.5 mgs of the formulation having a concentration of 50 mgper ml of 0.9% NaCl. In our jet-type nebuliser, the volume of drugrequired will be 1.05, but in a mesh type atomiser will be 0.35 ml.Other drug delivery apparatus will require different volumes accordingto their dead volumes.

A1AT is supplied as a powder requiring dilution with water. A two-partpackage such as is disclosed in FIG. 10 will be suitable for a supply ofthe drug dilutant.

Another drug is cyclosporine which is normally delivered by a nebuliserrequiring a lung dose of 100 mgs at a concentration of 125 mgs per ml.Normally, 500 mg of cyclosporine in 4 ml of propylene glycol must benebulised. A lung dose from the present invention is 50 mgs using only62 mgs of the same formulation.

The amounts supplied for a typical jet nebuliser will be 1.3 mls, andfor a mesh type atomiser 0.6 ml. Other drug delivery apparatus willrequire a different volume depending on its dead volume.

Budesonide is a corticosteroide with a high topical anti-inflammatoryactivity, it is important in the management of asthma. To be effectivesteroids must be delivered over long periods ranging from months toyears. However it is important to minimise the dose delivered as therecan be significant side effects on the adrenal function, calciummetabolism and growth rate in children. There are also local sideeffects including irritation in the throat, candidiosis, and dysphonia.

Budesionide for nebulisation is typically formulated as 1000 mg, 500 mgor 250 mg in 2 ml for conventional nebulizers.

A study in 125 children with asthma using the system disclosed in thispatent delivered three different regimes of a short duration (2-12weeks) high delivered daily dose 200 μg followed by a long duration(12-22 weeks) low daily dose delivered dose 50 μg. Their treatmentcompliance was monitored electronically and their asthma symptoms by theparents using a visual analogue score. The treatment compliance over thestudy was 80/90% and the asthma scores reduced from a baseline of1.23/1.27 to 0.23/0.43.

The study in 481 children with asthma using conventional nebulizersdelivered five different regimes. Nominal nebulizer doses were in therange 250/1000 μg daily and placebo over a 12 week period. Their asthmasymptoms by the parents using a visual analogue scores, the asthmascores reduced from 1.21/1.33 to 0.87/0.93.

The comparative data in table 1 shows that the system according to thisinvention improved asthma scores by approximately twice as much as theconventional nebulizer using a low long-term daily dose. This study mayindicate that an even lower daily dose may be acceptable when deliveredwith a high compliance system such as disclosed in this invention, inthe range 12-50 μg budesonide. When delivered from a formulation of 500μg/ml would required only 0.024/0.1 ml of formulation.

This invention can also be applied to other corticosteroides such asFluticasone currently delivered by conventional nebulizer in aformulation of 250 μg/2000 μg in 2.5 ml. A delivered daily dose in therange 6-50 μg may be required, from an 800 μg/ml formulation wouldrequire 0.0075/0.063 ml.

TABLE 1 Budesonide Nebulising Suspension Study results daytime asthmasymptom scores (Visual analogue range 0-3 where 0 is no symptoms)Improved Invention Conventional 250 μg 250 μg 500 μg 1000 μg System200/50 μg 200/50 μg Nebuliser Once Twice Twice Once 200/50 μg 6/18 12/12Placebo daily daily daily daily 2/22 weeks weeks weeks Baseline 1.271.21 1.31 1.33 1.28 1.23 1.26 1.27 at entry End of 1.08 0.93 0.91 0.870.91 0.23 0.43 0.36 Study Change 0.19 −0.28 −0.4 −0.46 −0.37 −1 −0.83−0.91

Other drugs suitable for use are antiviral/antiinfective drugs GammaInterferon (IFN*), Synagis™ Virazole® and SuperVent™, antifungal drugssuch as AmBiosome®, corticosteroids such as Budesonide®, Surfactantdrugs Exosurf® and Surfaxin™. Other drugs suitable for use are hormones,including growth hormone, Erythropoitin, Parathyroid Hormone,Lureinizing Hormone Releasing Hormone (LHRH). Also drugs for pulmonaryhypertension (PPH) including Iloprost, Flolan and UT15, and for paincontrol opiates and cannabinoids including Dronabinol (THC), Morphineand Marinol®.

Other drugs suitable are insulin for diabetics and Calcitonin forosteoporosis.

The invention claimed is:
 1. A drug delivery apparatus comprising: adrug delivery device for selectively delivering drug-laden air or airnot laden with the drug; a sensor for monitoring a breathing pattern ofa patient; a controller arranged to control the drug delivery devicebased on a length of at least one previous inhalation of the patient todeliver drug-laden air in pulses which begin when the patient ismonitored by the sensor to begin inhalation, the pulses having aduration which is adjusted by the controller on the basis of themonitored breathing pattern of the patient and the length of the atleast one previous inhalation, wherein the pulse duration is determinedbased upon a tidal volume and an end volume of the patient, and whereinif a monitored inhalation is not suitable for drug delivery thecontroller controls the drug delivery device to abort a pulsecorresponding to the monitored inhalation; a feedback indicator whichindicates to the patient whether a pulse of drug-laden air is currentlybeing delivered; a dose calculator which calculates a dose delivered tothe patient; an indicator which indicates to the patient when a desireddose has been delivered; and a drug formulation in which NaCl andtobramycin are dissolved in a solvent, wherein a delivery efficiency ofthe drug formulation is at least 80 percent.
 2. The drug deliveryapparatus according to claim 1, wherein the drug formulation includesabout 19 mg tobramycin and the solvent is about 0.3 ml in volume.
 3. Thedrug delivery apparatus according to claim 1, wherein the drugformulation further comprises an additional amount of between about 6and 50 mg tobramycin in about 0.1 to 0.8 ml solution which fills a deadvolume of the delivery apparatus and which is residual once all of thedrug which can be delivered has been delivered.
 4. The drug deliveryapparatus according to claim 1, wherein the concentration of tobramycinis about 60 mg/ml.
 5. A drug delivery apparatus comprising: a drugdelivery device for selectively delivering drug-laden air or air notladen with the drug; a sensor for monitoring a breathing pattern of apatient; a controller arranged to control the drug delivery device basedon a length of at least one previous inhalation of the patient todeliver drug-laden air in pulses which begin when the patient ismonitored by the sensor to begin inhalation, the pulses having aduration which is adjusted by the controller on the basis of themonitored breathing pattern of the patient and the length of the atleast one previous inhalation, wherein the pulse duration is determinedbased upon a tidal volume and an end volume of the patient; a feedbackindicator which indicates to the patient whether the monitored breathingpattern is effective for inhaling drug-laden air or not; a dosecalculator which calculates a dose delivered to the patient; anindicator which indicates to the patient when a desired dose has beendelivered; and a drug formulation including Alpha 1 Antitrypsin in anaqueous solution, wherein a delivery efficiency of the drug formulationis at least 80 percent.
 6. The drug delivery apparatus according toclaim 5, wherein the drug formulation includes about 12.5 mg Alpha 1Antitrypsin and the aqueous solution has a volume of about 0.25 ml. 7.The drug delivery apparatus according to claim 6, wherein the drugformulation further includes an additional amount of between 0.1 ml and0.8 ml of solvent.
 8. A drug delivery apparatus comprising: a drugdelivery device for selectively delivering drug-laden air or air notladen with the drug; a sensor for monitoring a breathing pattern of apatient; a controller arranged to control the drug delivery device basedon a length of at least one previous inhalation of the patient todeliver drug-laden air in pulses which begin when the patient ismonitored by the sensor to begin inhalation, the pulses having aduration which is adjusted by the controller on the basis of themonitored breathing pattern of the patient and the length of the atleast one previous inhalation, wherein the pulse duration is determinedbased upon a tidal volume and an end volume of the patient, and whereinif a monitored inhalation is not suitable for drug delivery thecontroller will control the drug delivery device to abort a pulsecorresponding to the monitored inhalation; a feedback indicator whichindicates to the patient whether a pulse of drug-laden air is currentlybeing delivered; a dose calculator which calculates a dose delivered tothe patient; an indicator which indicates to the patient when a desireddose has been delivered; and a drug formulation including Budesonide ina solvent, wherein a delivery efficiency of the drug formulation is atleast 80 percent.
 9. The drug delivery apparatus according to claim 8,wherein the drug formulation includes about 25 μg of Budesonide and avolume of the solvent is about 0.05 ml.
 10. A drug delivery apparatuscomprising: a drug delivery device for selectively delivering drug-ladenair or air not laden with the drug; a sensor for monitoring a breathingpattern of a patient; a controller arranged to control the drug deliverydevice based on a length of at least one previous inhalation of thepatient to deliver drug-laden air in pulses which begin when the patientis monitored by the sensor to begin inhalation, the pulses having aduration which is adjusted by the controller on the basis of themonitored breathing pattern of the patient and the length of the atleast one previous inhalation, wherein the pulse duration is determinedbased upon a tidal volume and an end volume of the patient, and whereinif a monitored inhalation is not suitable for drug delivery thecontroller will control the drug delivery device to abort a pulsecorresponding to the monitored inhalation; a feedback indicator whichindicates to the patient whether a pulse of drug-laden air is currentlybeing delivered; a dose calculator which calculates a dose delivered tothe patient; an indicator which indicates to the patient when a desireddose has been delivered; and a drug formulation including fluticasone insolution, wherein a delivery efficiency of the drug formulation is atleast 80 percent.
 11. The drug delivery device as recited in claim 1,wherein the pulse duration is calculated as:Pulse duration=mean inspiratory time×(mean tidal volume−end volume)/meantidal volume.
 12. The drug delivery device as recited in claim 5,wherein the pulse duration is calculated as:Pulse duration=mean inspiratory time×(mean tidal volume−end volume)/meantidal volume.
 13. The drug delivery device as recited in claim 8,wherein the pulse duration is calculated as:Pulse duration=mean inspiratory time×(mean tidal volume−end volume)/meantidal volume.
 14. The drug delivery device as recited in claim 10,wherein the pulse duration is calculated as:Pulse duration=mean inspiratory time×(mean tidal volume−end volume)/meantidal volume.